1554P - Clinical Impact of ERBB2 copy number and tumor mutation burden (TMB) in patients with HER2- positive advanced gastric cancer treated by nivolumab (N-mab) plus trastuzumab (T-mab) and standard chemotherapy

Background

We conducted a clinical trial evaluating safety and efficacy of T-mab plus N-mab with S-1/Capecitabine plus oxaliplatin (UMIN000034222). The aim of this study was to investigate the clinical significance of ERBB2 amplification (amp.) and TMB-H for this new combination therapy.

Methods

Patients were treated with S-1 80 mg/m2/day or Capecitabine 2000 mg/m2/day on days 1-14 with oxaliplatin 130 mg/m2, N-mab 360mg, and T-mab 8mg/kg for initial treatment, and subsequently with 6 mg/kg on day, repeated every 3 weeks. Pretreatment primary tumor samples were collected for whole exome sequencing (WES) and immunohistochemistry (IHC).

Results

Among 42 patients enrolled in this clinical trial, WES was performed on 23 patients. ERBB2 amp. (≥ 6 copies) was observed in 15 patients (65%). Fourteen (93.3%) of these 15 patients with ERBB2 amp. and 2 (25%) of 8 patients without ERBB2 amp. were IHC3+, respectively (p = 0.002). There was a weak positive correlation between ERBB2 copy number and PFS (r = 0.449, p = 0.032). Patients with ERBB2 amp. showed longer PFS than those without ERBB2 amp. (mPFS: 16.3 vs 5.8 months, HR = 0.70 [95%CI 0.24-2.09], p = 0.522). In particular, 7 patients with high ERBB2 copy number (≥ 50) showed remarkably longer PFS and a higher response rate than 16 patients with < 50 (mPFS: 20.8 vs 6.7 months, HR = 0.40 [95%CI 0.12-1.30], p = 0.117, response rate: 100% vs 63%, p = 0.124). TMB-H (≥ 10 muts/Mb) was observed in 6 patients (26%), and these patients also showed substantially longer PFS than those with TMB-L (mPFS: 16.3 vs 9.2 months, HR = 0.43 [95%CI 0.12-1.51], p = 0.172) with a comparable response rate (83% vs 73%). Eleven patients with ERBB2 copy number ≥ 50 or TMB-H showed significantly longer PFS (mPFS: 20.8 vs 5.8 months, HR = 0.28 [95%CI 0.09-0.88], p = 0.021) and OS (mOS: not reached vs 15.0 months, HR = 0.10 [95%CI 0.01-0.78], p = 0.007) and a higher response rate (91% vs 58%, p = 0.155) than the remaining 12 patients.

Conclusions

High ERBB2 copy number and TMB-H may be a candidate biomarker for this new combination therapy including T-mab and N-mab in patients with HER2-positive advanced gastric cancer.

Clinical trial identification

UMIN000034222.

Editorial acknowledgement

Legal entity responsible for the study

Daisuke Takahari.

Funding

Ono Pharmaceutical Co., Ltd.

Disclosure

H. Shoji: Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co., Ltd., Zymeworks inc.; Financial Interests, Institutional, Local PI: Ono Pharmaceutical Co., Ltd., MSD, Astellas, Amgen, Daiichi Sankyo; Financial Interests, Institutional, Funding: Ono Pharmaceutical Co., Ltd., Takeda Pharmaceuticals. K. Minashi: Financial Interests, Institutional, Research Grant: Amgen, Taiho Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd., Astellas Pharmaceutical Co., Ltd. H. Hara: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Boehringer Ingelheim, MSD; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, MSD, Ono, Bayer, Chugai, Lilly, Merck Biopharma, Taiho, Takeda, Yakult, Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Janssen, Merck Biopharma, MSD, Ono, Taiho, ALX oncology. N. Boku: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Eli Lilly, Ono Pharmaceutical, Taiho, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical, Ono Pharmaceutical. K. Yamaguchi: Financial Interests, Personal, Invited Speaker: Taiho; Financial Interests, Personal, Expert Testimony: Daiichi Sankyo, Bristol Myers Squibb, Ono, Eli Lilly Japan; Financial Interests, Institutional, Funding: Taiho. All other authors have declared no conflicts of interest.